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Natural MHC Class I Polymorphism Controls the Pathway of Peptide Dissociation from HLA-B27 Complexes

Kathrin Winkler ^*, Anja Winter ^*, Christine Rueckert , Barbara Uchanska-Ziegler  and Ulrike Alexiev ^*

^* Physics Department, Freie Universität Berlin, Berlin, Germany; and Institut für Immungenetik, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

Correspondence: Address reprint requests to Dr. Ulrike Alexiev, E-mail: alexiev{at}physik.fu-berlin.de.

Analysis of antigen dissociation provides insight into peptide presentation modes of folded human leukocyte antigen (HLA) molecules, which consist of a heavy chain, ß₂-microglobulin (ß₂m), and an antigenic peptide. Here we have monitored peptide-HLA interactions and peptide dissociation kinetics of two HLA-B27 subtypes by fluorescence depolarization techniques. A single natural amino-acid substitution distinguishes the HLA-B*2705 subtype that is associated with the autoimmune disease ankylosing spondylitis from the non-disease-associated HLA-B*2709 subtype. Peptides with C-terminal Arg or Lys represent 27% of the natural B*2705 ligands. Our results show that dissociation of a model peptide with a C-terminal Lys (GRFAAAIAK) follows a two-step mechanism. Final peptide release occurs in the second step for both HLA-B27 subtypes. However, thermodynamics and kinetics of peptide-HLA interactions reveal different molecular mechanisms underlying the first step, as indicated by different activation energies of 95 ± 8 kJ/mol (HLA-B*2705) and 150 ± 10 kJ/mol (HLA-B*2709). In HLA-B*2709, partial peptide dissociation probably precedes fast final peptide release, while in HLA-B*2705 an allosteric mechanism based on long-range interactions between ß₂m and the peptide binding groove controls the first step. The resulting peptide presentation mode lasts for days at physiological temperature, and determines the peptide-HLA-B*2705 conformation, which is recognized by cellular ligands such as T-cell receptors.

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